prostaglandin-d2 and Severe-Acute-Respiratory-Syndrome

The morbidity and mortality associated with respiratory virus infection is felt most keenly among the elderly. T cells are necessary for viral clearance, and many age-dependent intrinsic T cell defects have been documented. However, the development of robust T cell responses in the lung also requires respiratory DCs (rDCs), which must process antigen and migrate to draining LNs (DLNs), and little is known about age-related defects in these T cell-extrinsic functions. Here, we show that increases in prostaglandin D(2) (PGD(2)) expression in mouse lungs upon aging correlate with a progressive impairment in rDC migration to DLNs. Decreased rDC migration resulted in diminished T cell responses and more severe clinical disease in older mice infected with respiratory viruses. Diminished rDC migration associated with virus-specific defects in T cell responses and was not a result of cell-intrinsic defect, rather it reflected the observed age-dependent increases in PGD(2) expression. Blocking PGD(2) function with small-molecule antagonists enhanced rDC migration, T cell responses, and survival. This effect correlated with upregulation on rDCs of CCR7, a chemokine receptor involved in DC chemotaxis. Our results suggest that inhibiting PGD(2) function may be a useful approach to enhance T cell responses against respiratory viruses in older humans.

Topics: Aging; Animals; Cell Movement; Cellular Microenvironment; Coronavirus Infections; Dendritic Cells; Disease Susceptibility; Immunocompromised Host; Influenza A virus; Lung; Lymph Nodes; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Murine hepatitis virus; Orthomyxoviridae Infections; Prostaglandin Antagonists; Prostaglandin D2; Receptors, CCR7; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus; Specific Pathogen-Free Organisms; T-Lymphocyte Subsets